Synthesis of 15 oxygenated steroids



I own physiological action.

United States PatentfQ SYNTHESIS OF 15 OXYGENATED STEROIDS Josef Fried, New Brunswick, N. J., assignor to Olin .Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Application May ,27, 1955,

Serial No. 511,785

14 Claims. (Cl. 260-3973) The new steroids of this invention comprise: (a) 15- hydroxy-pregnane-3,20-dione; (b)

2,799,689 Patented July 16, 1957 ice allopregnane-3,20-diones are new steroids which are active as myotrophic or proteinanabolic agents. The pregnane-3,15,20-trione, allopregnane-El,15,20-trione, and allol4-iso-l7-isopregnane-3,15,20-trione derivatives are new steroids which are utilizable as androgenic agents.

' The following examples are illustrative of the invention'(all temperatures being in centigrade):

EXAMPLE 1 Catalytic hydrogenation of 15fl-hydroxypr0gesterone t0 15fl-hydroxypregnane-3,20-dione and JSB-hydroxyallopregnane-3,20-dione To a suspension of 100 mg. of 5% palladium on barium sulfate catalyst in 2 ml. of ethyl acetate is added a solution of 100 mg. of lSfl-hydroxyprogesterone in 7 ml. of-ethyl acetate. Hydrogen uptake is rapid and is complete within 17 min. The total uptake of 8.8 cc. of hydrogen corresponds to 1.16 moles/mole of substrate.

The catalyst is centrifuged off and washed several times with chloroform. The combined ethyl acetate-chloroform solution is evaporated to dryness in vacuo and separated by fractionalcrystallization from acetone into 15 -hydroxyallopreg- I nane-3,20-dione; (c) pregnane-3,15,20-trione; (d) allopregnane-3,15,20-trione; and '(e) allo-14-iso-17-isopreg: name-3,15,20-trione.

The new 15-hydroxypregnane-3,20-dione and-15-hydroxyallopregnane-3,20-dione steroids of this invention may be prepared by a process essentially comprising catalytically hydrogenating a 15-hydroxyprogesterone. The allopregnane-3,15,20-trione can be similarly prepared by catalytically hydrogenating IS-ketoprogesterone or by the oxidation of 1506- 0! 15/3-hydroxyallopregnane-3,20- dione. Pregnane-3,15,20,-trione can be prepared by the oxidation of 150: or l5 8-hydroxypregnane-3,20 dione. To prepare allo-l4-iso-17-isopregnane-3,15,20-trione, allopregnane-3,l5,20-trione is treated with a basic reagent. The IS-hydroxyprogesterohe and ,lS-ketoprogesterone steroids useful as starting materials in the processes of this invention can be prepared by the methods disclosed by Josef Fried et al. in their Patent No. 2,753,290, granted July 3, 1956, and applications Serial Nos. 511,781 and 511,782, filed on even date herewith.

To prepare the l5-hydroxypregnane-3,ZO-dione, 15- hydroxyallopregnane 3,20 dione and allopregnane- 3,15,20-trione derivatives of this invention, IS-hydroxyprogesterone (wherein the hydroxy group is in either the alpha or beta position) or 15-ketoprogesterone is catalytically hydrogenated by treatment with at least one mole of hydrogen per mole of steroid. Suitable hydrogenation catalysts utilizable in effecting this reaction are platinum, Raney nickel, and palladium, although any other knownhydrogenation catalyst may be employed. This reaction results in a mixture of 15-hydroxypregnane- 3,20-dione and l5-hydroxyallopregnane-3,20-dione (which can be separated by the procedure in Example 1), if a 15-hydroxyprogesterone is used as the initial reactant, and primarily allopregnane-3,15,20-trione if 15-ket-oprogesterone is used as the initial reactant. Pregnane-3,15,20- trione can be prepared by the oxidation of 15-hydroxypregnane-3,20-dione. To eifect this oxidation, the 15- hydroxy steroidis treated with an oxidizing agent such as a hexavalent chromium (chromic) ion, e. g., chromic oxide, preferably in an organic acid medium (e. g. glacial acetic acid). This oxidation procedure also affords an alternative route for the preparation of allopregnane- 3,15,20-trione from 15-hydroxyallopregnane-3,20-dione.

The 15-hydroxypregnane-3,20-diones and l5-hydroxy- 1Sfl-hydroiryallopregnane-S,20-dione and l5 3-hydroxypregnane-3,20-dione. The more insoluble allo-compound separates first and has the following properties: M. P. about 256-258, [a] |93 (c., 0.57 in chloroform). From the acetone mother liquor lSfl-hydroxypregnanedione is obtained, M. P. about 216218 By substituting 100 mg. of 15a-hydroxyprogesterone for the'ISfi-hydroxyprogesterone in Example 1, and fol- I lowingthe same procedure,. a mixture of l5a-hydroxyallopregnane-3,2 0-di0ne and 15a-hydroxypregnane-3,20-dione is produced, which mixture can be separated according to the procedure of this example.

7 EXAMPLE 2 Catalytic hydrogenation of IS-ketoprogesterone to allopregnane-3,15,20-tri0ne substrate has been absorbed. After centrifugation of the catalyst and removal of the solvent, the crystalline residue consisting of allopregnane-3,15,20-trione is recrystallized from alcohol. The pure substance has the following properties: M. P. about 220221; [(11 +137 (c., 0.58 in CHCla) (c., 0.50 in methanol);

Ami? 5.75 (15-keto), 5.82 5.85;; (3- and 20-keto) Analysis.Calcd. for C21H3o0s(330.45): C, 76.32; H, 9.15. C, 76.76; H, 8.93.

EXAMPLE 3 Oxidation of 15p-hydroxypregnane-3,20-di0ne t0 pregnane-3,15,20-tri0ne To a solution of 25 mg. of 15B-hydroxypregnane-3,20- dione in 3 ml. of glacial acetic acid is added over a period of ten minutes a solution of 7.5 mg. of CrOa in 3 ml. of glacial acetic acid. The excess chromic acid is destroyed by the addition of 0.5 ml. of alcohol and the mixture concentrated to small volume in vacuo. The residue is taken up in chloroform and the chloroform solution extracted with Water, dilute sodium bicarbonate and again with water. Evaporation of the solvent in vacuo leaves pregnane-3,15,20-trione as a residue, which after crystallization from 95% ethanol melts at about 167-169 C.

Similarly 15a-hydroxypregnane-3,20-dione yields pregmane-3,15,20-trione upon oxidation in accordance with the procedure of this example.

EXAMPLE 4 Oxidation of 155-h droxyallopregnane-fi,ZO-dione to allpregnane-3,15,20-trione EXAMPLE 5 Isomerization of all0pregnane-3,15,20-trione t0 allo-14- iso-I 7-iso-pr1egnane-3J 5 ,ZO-trione A solution of 10 mg. of allopregnane-3,15,20-trione in 2 ml. of of 0.02 N KOH in methanol is allowed to stand at room temperature for 20 hours. During this period of time the specific rotation changes from +l30 to +53. Acidification of the cquilibrated solution with one drop of acetic acid followed by evaporation of the solvent furnishes a residue, which is extracted with chloroformand Washed with water. Evaporation of the chloroform affords crystals, which on recrystallization from acetonehexane give pure allo-14-iso-17-isopregnane-3,15,20-trione, M. P. about 186-189; [a] +60 (c., 0.56 in CHCla);

Nuiol 5.76 (15-keto), 5.85;. (3- and -keto) Analysis.Calcd. for C21Hao0a (330.45): C. 76.32; H, 9.15. Found: C, 76.32; H, 8.91.

Allo-14-iso-17-isopregnane-3,15,20-trione can also b termed 21110-143,17a-pregnane-3,15,20-trione and can be represented by the formula CHI This invention may be variously otherwise embodied within the scope of the appended claims.

Iclaim:

1.' A steroid selected from the group consisting of: 15- hydroxypregnane 3,20-dione; IS-hydroxyallopregnane- 3,20 dione; pregnane-3,1S,20-trione; allopregnane-3,15, 20-trione; and allo-14-iso-17-isopregnane-3,15,20-trione.

. 15-hydroxypregnane-3,20-dione.

. 15-hydroxyallopregnane-3,20-dione.

. Pregnane-3,15,20-trione.

. Allopregnane-3,15,20-tri0ne.

. A11o-14-iso-17-isopregnane-3,15,20-trione.

. The process for preparing a steroid of the 3.20-diketopregnane series having in the 15-position a substituent selected from the group consisting of hydroxy and keto; which comprises reacting a steroid selected from the group consisting of 15-hydroxyprogesterone and 15- ketoprogesterone with hydrogen in the presence of a hydrogenation catalyst of the group consisting of platinum, Raney nickel and palladium, and recovering the desired steroid.

8. The process for preparing a steroid selected from the group consisting of 15-hydroxypregnane-3,20-dione and l5-hydroxyallopregnane-3,20-dione, which comprises reacting a 15-hydroxyprogesterone With hydrogen in the presence of a hydrogenation catalyst of the group consisting of platinum, Raney nickel and palladium, and recovering the desired steroid.

9. The process for preparing allopregnane-3,15,20-trione which comprises reacting 15-ketoprogesterone with hydrogen in the presence of a hydrogenation catalyst of the group consisting of platinum, Raney nickel and palladium, and recovering the steroid thus produced.

10. The process for preparing allopregnane-3,15,20-trione, which comprises reacting a IS-hydroxyallopregnane- 3,20-dione with a hexavalent chromium compound and recovering the l5-ket0 derivative thus formed.

11. The process for preparing pregnane-3,l5,20-trione, which comprises reacting a 15-hydroxypregnane-3,20-dione with a hexavalent chromium compound and recovering the IS-keto derivative thus formed.

12. The process for preparing allo-14-iso-17-isopreg nane-3,l5,20-trione, which comprises reacting allopregnane-3,15,20-trione with potassium hydroxide, and recovering the isomeric derivative thus formed.

13. The process of claim 12 wherein the reaction is carried out in an organic solvent.

14. The process of claim 12 wherein the reaction is carried out in a lower alkanol solvent.

, No references cited. 

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF: 15HYDROXYPREGANE - 3,20-DIONE; 15-HYDROXYALLOPREGNANE3,20 - DIONE; PREGNANE-3,15,20-TRIONE; ALLOPREGNANE-3,15, 20-TRIONE; AND ALLO-14-ISO-17-ISOPREGNANE-3,15,20-TRIONE. 